From a regulatory point of view the main aspects of stability purely concern the product, namely consistent characteristics of the product (for example consistent glycoforms and more generally, in-vivo activity).
However, from a manufacturing point of view, important aspects of stability are naturally product quality but also consistent growth and productivity of the producing cell line clone. For example, from Lonza™ guidelines, a change of over 30% in product titre over 40 doublings (roughly 10 passages) is deemed an unstable cell line.
Changes in the cell line can be attributed to changes in gene copy number, mRNA copy number and underlying changes to the cell on the whole (i.e. changes to proteome and metabolome). Changes to a cell's genome implies a degree of phenotypic genetic instability, or a “mutator phenotype” (Loeb et al 1999). It is likely that any cell line clone which has become this phenotype will be subject to other linked changes in phenotype.
It is an object of the invention to overcome at least one of the above-referenced problems.